Abstract
The extension of life span by caloric restriction has been studied across species from yeast and Caenorhabditis elegans to primates. No generally accepted theory has been proposed to explain these observations. Here, we propose that the life span extension produced by caloric restriction can be duplicated by the metabolic changes induced by ketosis. From nematodes to mice, extension of life span results from decreased signaling through the insulin/insulin-like growth factor receptor signaling (IIS) pathway. Decreased IIS diminishes phosphatidylinositol (3,4,5) triphosphate (PIP3 ) production, leading to reduced PI3K and AKT kinase activity and decreased forkhead box O transcription factor (FOXO) phosphorylation, allowing FOXO proteins to remain in the nucleus. In the nucleus, FOXO proteins increase the transcription of genes encoding antioxidant enzymes, including superoxide dismutase 2, catalase, glutathione peroxidase, and hundreds of other genes. An effective method for combating free radical damage occurs through the metabolism of ketone bodies, ketosis being the characteristic physiological change brought about by caloric restriction from fruit flies to primates. A dietary ketone ester also decreases circulating glucose and insulin leading to decreased IIS. The ketone body, d-β-hydroxybutyrate (d-βHB), is a natural inhibitor of class I and IIa histone deacetylases that repress transcription of the FOXO3a gene. Therefore, ketosis results in transcription of the enzymes of the antioxidant pathways. In addition, the metabolism of ketone bodies results in a more negative redox potential of the NADP antioxidant system, which is a terminal destructor of oxygen free radicals. Addition of d-βHB to cultures of C. elegans extends life span. We hypothesize that increasing the levels of ketone bodies will also extend the life span of humans and that calorie restriction extends life span at least in part through increasing the levels of ketone bodies. An exogenous ketone ester provides a new tool for mimicking the effects of caloric restriction that can be used in future research. The ability to power mitochondria in aged individuals that have limited ability to oxidize glucose metabolites due to pyruvate dehydrogenase inhibition suggests new lines of research for preventative measures and treatments for aging and aging-related disorders. © 2017 The Authors IUBMB Life published by Wiley Periodicals, Inc. on behalf of International Union of Biochemistry and Molecular Biology, 69(5):305-314, 2017.
Highlights
Increased ketone body concentrations occur during caloric restriction in widely different species ranging from Caenorhabditis elegans [9] to Drosophila [4] to man where ketone bodies are produced in liver from free fatty acids released from adipose tissue [10]
Most notable are a gradual increase in blood sugar and blood lipids, increased narrowing of blood vessels, an increase in the incidence of malignancies, the deterioration and loss of elasticity in skin, loss of muscular strength and physiological exercise performance, deterioration of memory and cognitive performance, and in males decreases in erectile function
Many aging-induced changes, such as the incidence of malignancies in mice [82], the increases in blood glucose and insulin caused by insulin resistance [39,78], and the muscular weakness have been shown to be decreased by the metabolism of ketone bodies [18,83], a normal metabolite produced from fatty acids by liver during periods of prolonged fasting or caloric restriction [12]
Summary
In 1935, McCay et al showed that caloric restriction of 30% to 50% increased the average life span of rats from 500 to 820 days [1]. Increased ketone body concentrations occur during caloric restriction in widely different species ranging from Caenorhabditis elegans [9] to Drosophila [4] to man where ketone bodies are produced in liver from free fatty acids released from adipose tissue [10]. In contrast to the metabolism of D-bHB, which produces only NADH, the further metabolism of the L-form is metabolized by the fatty acid b-oxidation system, which results in the reduction of one mitochondrial NAD and one co-enzyme Q with no increase in redox span between the two couples and no increase in the DG0 of ATP hydrolysis. Many of the signaling pathways mediating extension of life span have been determined by geneticists largely by work using the short-lived nematode C. elegans
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